JPS5852294A - Cephalosporin antibiotic and medicinal preparation - Google Patents

Abstract

NEW MATERIAL:A compound of formulaI[R1 is formula II and III; R2 is formula IV (R3 is Cl, NO2, alkoxy), -OR4 (R4 is 1-4C alkyl), -OCH2OR4]. EXAMPLE:4-Chlorophenyl 7-(thiophene-2-acetamide)cephalosporanate. USE:An antibacterial that develops antibacterial activity, only when it is absorbed in bodies, thus causing no microbism substitue. PREPARATION:For example, the reaction of 7-aminocephalosporanic acid of formula V or its sodium salt with thiophene-2-acetyl chloride is carried out in water-acetone mixed solvent in the presence of an alkali metal. Then, the reaction with 4-chlorophenol follows the above reaction, in the presence of N,N- dicyclohexylcabodiimide in a solvent such as tetrahydrofuran to give the compound of formulaI.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to cephalosporin antibiotics and drugs thereof. In detail, we have introduced antibiotics and cephalosporin-like activities, which are characterized by chemically modifying cephalosporin antibiotics, which cause them to lose their antibacterial activity, but regain their antibacterial activity once absorbed into the body. Relating to drugs that have.

Cephalosporin antibiotics are currently widely used and are excellent drugs due to their selective toxicity towards laIl.

However, since it has an antibacterial effect on the beneficial lI flora resident in the living body, it has the serious drawback of disturbing the flora in the living body, especially in the intestines. The case is remarkable.

As a result, diseases such as bacterial alteration may occur, and in some cases, colitis and diarrhea may occur.◎ The present inventors have diligently investigated antibiotics with cephalosporin-like activity that do not have these drawbacks. , general formula (1
) was found to be effective, leading to the present invention〇 Therefore, an object of the present invention is to provide a cephalosporin derivative that is useful as an active ingredient of a cephalosporin antibacterial agent. There is a particular thing.

The present invention will be explained in detail below.

The characteristics of the present invention are general formula (1), C! OR.

(In the formula, R1 is 01.-No! or -0R4 (In the formula, R
4 is H, C! 1 to C4 alkyl group or salt) in the cephalosporin derivatives shown in the table.

A feature of the present invention is an antibacterial agent containing a cephalosporin derivative represented by the above general formula (1) as an active ingredient. The compound represented by the general formula (1) [hereinafter referred to as the substance] can be obtained by chemically modifying a cephalosporin antibiotic, but it does not affect the indigenous bacterial flora of the body when administered. It is a completely new type of antibiotic that has antibacterial activity only after it is absorbed into the bloodstream and enters the bloodstream.It is also an extremely safe substance with low acute toxicity.

This substance can be obtained by the following method.

(a) Formula (■): 7-(thiophene-2-acetamido)cephalosporanic acid, its salt, or chloride is mixed with an organic solvent such as DMIF% acetone, benzene% [methylene, pyridine, TH? , dioxane 1 Dissolved in triethylamine, etc. In this case, it is preferable to add carbondiimide ethyl chloride or oxalyl chloride as an activator.

This system has a general formula (Buttonomi) [In the formula, X is 10H or -MH, and R3 is cl.

7 Not # -OR< (in the formula, R4 has the same meaning as above) or -0OOR4 (limited to the case where R- is in the ortho position with respect to the position of X. In the formula, R4 has the same meaning as above) ] Or general formula ■: X0H1oFt4□ (IV
) (wherein,
Allow to react for 48 hours. After the reaction, the desired product is collected from the reaction system by means such as solvent washing, solvent extraction, and recrystallization.

A solution of a compound represented by 7-amitsuse 7 allosboranic acid, water and acetone in acetone is added dropwise,
React at -30 to 40°C for 0.5 to 48 hours. After the reaction is completed, the target product is collected from the 1# reaction system by solvent washing, solvent extraction, recrystallization, etc.

7-Amitusephalosboranic acid represented by or gelaldehyde represented by sodium is reacted at -20 to 50°C to 0.
React for 5 to 48 hours. ◎After the reaction, the target product is collected from the reaction system by means such as solvent washing, solvent extraction 1 and recrystallization.

(d) The substance in the form of a lactone has the corresponding 7
- Monosubstituted cephalosporanic acid can be produced by stirring in a mixed bath medium of hydrochloric acid and dioxane.

The pharmacological effects of this substance were investigated as follows.

(d) Acute toxicity The acute toxicity was investigated by intraperitoneal and forced oral administration using ICR-JCL mice.1 The substance was dispersed in physiological saline for both intraperitoneal and oral administration, and the substance was administered via a syringe or into the stomach. The dose was adjusted to the prescribed amount using a probe.

After administration, the symptoms of toxicity were continued to be observed, and the LDle value was determined from the historical mortality rate up to the 7th day. The findings were obtained through autopsy in both surviving and dead cases. LDl, value is Lichff.

Yield Quillcoxono (Li$chfield-1
4/1l--#coxon) Obtained by graphic calculation method.

All results are LD regardless of intraperitoneal or oral administration, and the value is s.
o 'I / was 1 or more.

In addition, the LD of cephalodene sodium as a comparative example,...l51
It is understood that this substance is safe since it is 1/'Q or more.

(1) Effects on Enterobacteriaceae were cultured at 25°C or 37°C for 1 to 5 days and examined for Escherichia coli, Pseudomonas aeruginosa, Streptococcus, Lactic acid bacteria, Bifidobacteria, and Bacterioids.

There was almost no difference in the number of each of the above bacteria before and after administration of this substance. It was found that it did not affect the intestinal flora.

(→ Antibacterial activity was investigated in accordance with the standard method of the Japanese Society of Chemotherapy.The minimum inhibitory concentration (1011) was used as the test bacteria. MIC) sought 0 genuine 11)! - (In order to prove that the activity changes when absorbed into the body, the following experiment was conducted using a metabolic activating enzyme [rat liver homogenate) (referred to as 8-9 mix).

eta h 1ococcus aureus I
AM 1011 preculture solution H) Adjust Nco/d, 5
It was added to 0 times the volume of Mueller-H1nton agar medium and plated.

A penicillin tube with a diameter of 8 nm was placed on a flat plate, and 0.1 d of the present substance or a culture of the present substance and 8-9 ml was added thereto, and cultured at 37°C for 18 hours, and the diameter of the growth inhibition circle was measured.

For comparison, if the diameter of the growth inhibition circle of cephalothin sodium is 100, that of the system containing only this substance is 0 to 3.
It was 3. - That of the system of strength wood material + 8-9mlx was 1 to 66.

This indicates that although this substance has low antibacterial properties as it is, it is activated by enzymes when it enters the body.

(→ Effect on infectious diseases In order to confirm that it is activated in vivo, we conducted therapeutic experiments on infectious diseases using this substance.

8 in Escherichia intraperitoneally to 20 mice in each group.
After inoculation and infection with 11P'O, each of the present substances was orally administered at 5004/kf immediately after infection and 4 hours later, and the presence or absence of death due to infection was determined on the 7th day. The non-treated group had 9 deaths on the second day, whereas all of the substances showed a survival rate of 35% or more, indicating that they are effective as oral anti-infective agents.

As mentioned above, this substance is safe, has no effect on the intestinal i11 flora, and can be said to be a new cephalosporin antibiotic that enters the body and becomes active.

Since it is converted into cephalosporin antibiotics in vivo, it can be used as a Kl agent, which is in the same field as cephalosporin antibiotics.

The present substance can be further used in unit dosage form as a pharmaceutical composition containing at least one cephalsporin represented by general formula (1) and a pharmaceutically acceptable carrier diluent or auxiliary agent. These can be administered by oral, injection or rectal administration.

For oral administration, tablets, capsules, powders, granules, and powders are available.

It can be in the form of pills, ampoules, etc.

These are fillers, extenders, wetting agents, and disintegrants.

Binders, dissolution slowing agents, resorption enhancers, adsorption carriers.

Includes lubricants, etc. Specifically, starch, mannitol,
Silicic acid, cellulose derivative, 4 Latin, alginate,
Glycerin, agar, calcium carbonate.

Sodium bicarbonate, paraffin, quaternary ammonium compounds, glycerin monostearate, kaolin.

Examples include bentonite, Merck, potassium stearate, magnesium stearate, and polyethylene glycol. Also used as a pharmaceutical emulsion,
# It may be in the form of a liquid or a suspension.

The herbal medicine may contain polyethylene glycol and fatty acids or esters thereof.

Silica tablets, eliquicools, may be used as liquid compositions containing an inert diluent such as water or paraffin and suitable for oral administration. They may also contain adjuvants such as wetting agents, sweetening agents, and flavoring agents. (1) Compositions used for injectable administration may be sterile and may be aqueous or non-aqueous solutions, suspensions, or emulsions. Common examples include propylene glycol, polyethylene glycol, olive oil, and the like.

When used as a composition, this material contains 0.0% as an active ingredient. O
One place can contain 99.5% usually o, i to 90%.

This substance is used in a similar way to cephalosporin antibiotics and is useful in the treatment of bacterial infections. The dosage of the drug varies depending on the degree of infection and the condition of the patient, but in general, it is administered in 0.1 to 1 liter per adult patient per day (divided into several doses).

This will be explained below using examples.

Example 1 7-(thiophene-2-acetamido)cephalosphoranic acid 2. Of, 4-chlorophenol 0.65f, and N + N'-dicyclohexylcarbodiimide 1.
05 Dissolve F in 100% of tetrahydrofuran 1. The solution was stirred at room temperature for 24 hours. After removing the resulting 9N,N'-dicyclohexylurea, the solvent of solution F was distilled off, and the residue was dissolved in chloroform 100%. It was dissolved in The chloroform solution was washed with 5% hydrochloric acid, a 15X aqueous sodium bicarbonate solution, and water, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was recrystallized from ethyl acetate-n-hexane to obtain 1.4r crystals (yield 55%) with a melting point of 170-172°C.

The elemental analysis value is 0IIHI-010, N, calculated value as 8 dew O; 52.12. Hi 3.75,
N i 5.53 Actual value (2) Oi 52.09.
Hi 3.74 and Ni 5.54 were obtained.

Example 2 00H rich 7-(thiophene-2-acetamido)cephalosporanic acid 2.0ts 2-methoxyphenol 0.62
t and N,N'-dicyclohexylcarbodiimide 1
．． 05f was dissolved in 100- of tetrahydrofuran, and the solution was stirred at room temperature for 24 hours to produce 7tc+, 9N, N
'-After removing dicyclohexylurea.

The solvent of solution F was distilled off, and the residue was dissolved in 100% chloroform. Add the chloroform solution to 5% hydrochloric acid water s s
After washing with an aqueous sodium bicarbonate solution and water, drying over anhydrous magnesium sulfate and distilling off the solvent, the residue was recrystallized from ethyl acetate-n-hexane to obtain 1. The zero melting point at which crystals of sr (yield 72%) were obtained was 148-149°C.

The elemental analysis value is c, H110? Calculated value ■ Ci 54.98. E i 4.38. Ni
5.58 Actual value ■ Oi 54.93. Hi 4.
37. N i 5.51 and 6 nines.

Example 3 7-(thiophene-2-acetamido)cephalosporanic acid 2. Of, 4-nitrophenol 0.7t and N
, 1.05F of N'-dicyclohexylcarbodiimide was dissolved in 100 sd of tetrahydro7ran, and the solution was stirred at room temperature for 24 hours. After removing the generated N,N'-dicyclohexylurea and dying, the solvent of solution F was distilled off, and the residue was dissolved in 100ml of chloroform.The chloroform solution was washed with 5% hydrochloric acid and water, and then dissolved in sulfuric anhydride. After distilling off the solvent dried over magnesium, the residue was recrystallized from ethyl acetate-n-hexane to obtain 1. ar (yield 50%
) The melting point of the obtained crystal was 174-175°C. The elemental analysis value was calculated as C1 tomium Jsolalsl (to) Oi 51.06. H; 3.6B, Ni
8.12 Actual value (To) Oi 51.01. Hi 3
．． 61. The N gate was 8.07.

Example 4 1.3Of salicylaldehyde was added to a solution of 2.94V of sodium 7-amitusephalosboranate dissolved in 100% of methyl alcohol and stirred at room temperature for 2 hours. After distilling off the solvent, the residue was dissolved in ethyl alcohol. It was dissolved in lO- and treated with F. The V solution was added dropwise to 200 kg of n-hexane with stirring, and after 901 hours, the precipitated yellow crystals were scraped off, washed with 30 kg of n-hexane, and dried at room temperature for 4 hours at 10 kg of Hg. 2.51 t (yield: 63%) of crystals were obtained. The melting point was 199-202°C (decomposition).

The elemental analysis value is calculated as 011H1g01N18Na (2) Oi 51.26 Hi 3.77 N
; 7.04 actual value (to) O; 51.08 Ni
3.74 Ni was 2.06 Example 5 1 3.74f of 7-(adamantane-1-amido)cephalosporanic acid was dissolved in 2N aqueous hydrochloric acid solution 50- and dioxane 5
A solution dissolved in a mixed solvent of 0- was stirred at room temperature for 16 hours. The resulting crystals were collected, washed twice with water, and then recrystallized with acetonitrile-dimethylformand (ssl 1 volume ratio) to give a colorless product. needles II & t, z1r (yield 65%
) was obtained. The melting point was 240-242°C.0 Elemental analysis value is calculated as C1・Hl, 04N, 8) Oi 60.96 Hi 5.88 N; 7
．． 49 Actual measurement value (1) Oi 60.90 Hi 5.
81 N i 7.4 trowel.

Example 6 aoocH, oa Umugi H6 7-(thio7ene-2-7cetamido)cephalosporan @ 158011F is dissolved in 10-DMIF 0 then 404119 triethylamine is added and then 75%
6 ml of chloromethyl ethyl ether was added and stirred for 1 hour. After the reaction was completed, the reaction solution was extracted twice with 80% of methylene chloride in 100% of water, and the methylene chloride layer was washed with an aqueous solution of I No NILH (30%) and then washed with water (50mg). After adding Mg804 to the methylene chloride layer and drying, the solvent was removed under reduced pressure.The obtained crude crystals were recrystallized from methylene chloride-〇-hexane to give 139
The yield was 79%, yielding 9 q of product. The melting point is 14
The temperature was 8-150°C.

Infrared absorption spectrum &l mal 3-' (KBr
) 1782, 1745. 1722 Ultraviolet absorption spectrum λmax (aacxs) 61 Elemental analysis value (2) Stem theoretical value 0; 50.21 H; 4.88 N i
6.16 Actual value Oi 50.2 H; 4.7
Example 7 2.72 F of borane acid 7-aminocephalosporanic acid and 1.68 F of sodium bicarbonate were mixed with 30 F of water and 2 F of acetone to give a N i of 6.3.
1-adamantanecarboxylic acid chloride 2. An acetone solution of (5-) was added dropwise with stirring at 0°C. The reaction mixture was stirred at 0°C for 1 hour and at room temperature for 1 hour. After being left at room temperature overnight, the reaction solution was adjusted to pH 4 with IN hydrochloric acid. The formed crystals were extracted with ethyl acetate 200%. The extract was washed twice with water and dried over anhydrous magnesium sulfate, and the ethyl acetate was distilled off. The residue was dissolved in a mixed solvent of D-hexane and ethyl acetate. Recrystallization was carried out to obtain 2.51 t (yield: 58X) of white powder. The melting point was 195-197°C.

Is the elemental analysis value 0ntHssOs? Calculated value as Jx8 (
To) Oi 58.06 Hi 5.99 N i
6.45 Actual value (2) Oi 5g, 05 Hi 5.
87 N j 6.41 Example-8 coocas? -(joffene-2-acetamido)cephalosporanic acid 2-Ots Methyl 2-aminobenzoate 0.71
f and N,N'-dicyclohexylcarbodiimide 1.05F was dissolved in 10011t of tetrahydrofuran.1 The solution was stirred at room temperature for 24 hours.O produced N,
After removing N'-dicyclohexylurea, the solvent of 10 liquids was distilled off, and the residue was dissolved in 100% of chloroform. The chloroform solution was washed with a 5% aqueous hydrochloric acid solution and water, then dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was recrystallized with a mixed solvent of ethyl acetate and n-hexane to obtain 0.92 t (yield 35X) of crystals ◎ Melting point was 219-220°C ◎ Red Outer absorption spectrum/I/W m1LX* OII
'(KBr)3280.1792.1?40,16
75,1658,1537.1235 Ultraviolet absorption spectrum 1ml1Ll nm (011ON)232.273
, 311 elemental analysis value, calculated value as '44HmmOYkhB proverb (
) Oi 54.44 Hi 4.35 N i
7.94 actual value (to) O954, I Hj4.2
It was N28.0.

Example 9 Each of the above drugs was administered to a group of 5 mice (6 weeks old) at a dose of 500! The drug was orally administered for 2 days every day.

The administered cocoon and the feces of each mouse were collected 18 days after administration, diluted with 100 times the amount of anaerobic dilution & (9-phosphate buffer), and ground. Apply to the culture medium of each measured image shown and culture at 37°C or 25°C for 1 to 5 days aerobically or anaerobically (anaerobic glove box method).
, to measure the numbers of Escherichia coli, Pseudomonas aeruginosa, streptococci, lactic acid bacteria, bifidobacteria, and Bacteroidetes.Table 1: Medium and culture conditions used in the measuring cylinder Name Medium Culture conditions Colon 11i DHL agar 37°C aerobic 1 day record Pythoma li NAOagar 37°C aerobic 1 day record Pythemia bulb @ TATAOagar 37
℃ Aerobic 1 mortar hole Acid bacteria LB day agar 3
7℃ Anaerobic 5 days Bifidus B8 agar
37℃ Anaerobic 5 days Bacteroides NBGT
agar 37°C Anaerobic 5 day results are shown in Table 2.

As is clear from this table, an increase in Escherichia coli was observed in the cephalothin administration group, but for each of these substances, lactic acid bacteria decreased for 0 and 1 cephalothene, which had no change in Atb from before administration, whereas for each of these substances, the number of E. coli bacteria decreased. No different from lactic acid bacteria before administration.

Example 1O Antibacterial activity was measured by the agar plate dilution method in accordance with the standard method of the Japanese Society of Chemotherapy.

Test method Test bacterium Ksherichia coli IFO127
34eta h 1ococcua aureua M M 1011 The above strain was transformed into Mualler-H1nto
After inoculating into n medium and culturing at 37°C for 18 to 48 hours,
The test bacteria solution was mixed with li4!I to 10".

Mu
One agar plate was prepared by adding 1/9 amount of each to Eller-H1nton medium. Approximately 2 lines of the above-mentioned solutions G and S were applied to each plate using a platinum loop, and then 37°C for 18 hours to 24 hours was applied.
The results are shown in Table 3, where the concentration at which growth was completely inhibited was defined as the minimum growth inhibiting concentration.

Table 3 Example 11 Model experiment to prove that it is activated in the body The following method was used to use rat liver homocyne (S-9, manufactured by Oriental Yeast Co., Ltd.) as a metabolic activating enzyme. It was used with the following composition (hereinafter referred to as S-9m1x).

[Composition in l-]

89 0.5sd KO13,3/JmOI MgC11,6H10,8pmOL exucose-s-phosphate sp
moINADH 4 pmol NADPH 4 pmol 0.2M phosphate buffer (pH 7,4) 0.5 ml Sample liquid 0
．． Mix 1- and 8-9 mix O,9- or 0.1M phosphate buffer 0.9- as a control and incubate at 37°C for 2
9. Incubate with shaking for 0 minutes and conduct a sensitivity test.

8ta h 1000cOu#aur8uJ EngineeringAj41
011 into Mueller-H1nton medium,
After culturing at 37° C. for 18 hours, the cells were mixed with 50 times the volume of Mueller-H1nton agar medium at 10·/dKg and plated. Place a penicillin cup (diameter 8 cm) on top of the cup, add 0.1 - of the above reaction solution and leave it at 4°C for 2 hours≠
The cells were cultured at 37°C for 18 hours, and the diameter of one growth inhibition circle was measured.

The results are shown in Table 1g4.

Table 4* However, here, the following classifications are shown based on the activity values of the starting materials under the same conditions.

-〇X ± 0~IX + 1~33% 10 + 33~66
chiaooll IFO127341, 4X10' was intraperitoneally inoculated and infected, and this substance was orally administered at 5ooq/11 twice immediately after infection and 4 hours later, and the presence or absence of death due to infection was observed for 7 days. In all cases, 9 died on the second day of infection, but in all groups administered with this substance, on the seventh day after infection, more than 35% of the animals survived.

Example 13 [1] Tablet This substance obtained in Example 1 175 mf lactose
1611 starch
5Mg Hydroxyglobil Cellulose 3
．． 0Ilf Magnesium stearate 1.0 cape (2ooq/tablet) Mix this substance and lactose, add hydroxyglobil cellulose aqueous solution, knead, dry and pulverize. 0Add stearic acid pre-dispersed in starch to this pulverized product. Add and mix magnesium and compress into tablets using the usual method.

[2] Nine substances obtained in Granule Example 2 17619 Milk @
1619 starch
419 Hydroxyprobyl cellulose
41q Mix this substance, starch, and lactose, add hydroxyglobil cellulose aqueous solution, mix once, dry and crush. Granules were obtained by sieving in the range of 12 to 48 meshes.

Agent, Yoshio Kawaguchi Procedural Amendment 1981 1014. rr Japan Patent Office Commissioner Shima 1) Haruki Tono1, Indication of the case 1981 Patent application @1498682, Name of the invention
Relationship between cephalosporin antibiotics and their pharmaceutical agents 3 and the amended case Patent applicant 4, Agent 1-1 Shinjuku, Shinjuku-ku, Tokyo
No. 4 Yamada Building (zip code 160) Telephone (03) 35
No. 4-8623 5゜Nose ♂ Increased by the amendment 1, subject of amendment Specification 8, Contents of amendment (1) Page 8 of the middle chain of the specification is amended 9 times by attaching it.

(2) Pages 15 to 17 of the middle curtain of the specification are amended as shown in the attached sheet.

(3) @Page 19 of the specification is amended as shown in the attached sheet.

(4) Pages 21 and 22 of the middle part of the specification should be amended by adding separate sheets.

(6) Page 24 of the W14 detailed document is amended as shown in the attached sheet.

(6) Page 25, line 4 of the specification “ν@@g, em-”
There is J [shi, &! (am-ri).

(7) Page 25, line 6 of the specification [λ, @z, nm
J is corrected as [λ, , -, (m+)J.

A solution of the compound represented by the above in a7tone is added dropwise and reacted at -30 to 40°C for 0.5 to 48 hours. After completion of the reaction, the target product is collected from the reaction system by means such as solvent washing, weaving extraction, recrystallization, etc.

(a) Formula: %Formula % 7-Annocephala tetrasugillanic acid or an aldehyde represented by sodium and -48
Allow time to react. After the reaction, the target product is collected from the axillary reaction system by means of solvent washing, solvent extraction, and recrystallization.

(d) The substance in the lactone O form has the corresponding 7
- Substituted cephalosporanic acid can be produced by stirring in a base solvent of hydrochloric acid and dioxane.

Example 1 7-(thio7ene-acetoazdo)cephaa sulfonelll0#, 4-/tetralyphenol O0.Sl, and N,N'-dicyclohexylcarbosiimide 1
．． 05 Jll was moated into Tetracht-7tsun100-,
The solution was stirred at room temperature for 24 hours. Generate 9N, N'-
After removing the dicyclohexyl flare, the solvent of the film was distilled off, and the residue was poured into 100% amform.

After washing 5ill of proform with 5-hydrochloric acid water, 5-sodium bicarbonate water and water, it was dried over anhydrous magnesium sulfate. After distilling off sm, the residue was recrystallized from ethyl acetate-n-hexane to give 1.4# (yield: 551
Crystals of 1) were obtained. The melting point was 170-172°C.

The original IA analysis value is calculated as Co as C10mNmBm (1 C; 81L12, H; 3.7s,
N; 153 actual measurement value (@C; !!LO9, H; 3.
74, N; 5.54, 9.

Example 2 7-(thiophene-2-a-7-do)-7-fer-spotunate 2.61, 2-methoxyphenol 0.621 and N,N'-dicyclohexylcarboxylic acid 2-do 1.0!
! # was dissolved in 10G of tetrahydrofuran, and the solution was stirred at room temperature for 24 hours. After removing the generated 9N,N'-dicyclohexylurea, the rim solvent was distilled off,
The residue was dissolved in 100% chloroform. The chloroform concentrate was washed with S-hydrochloric acid solution, 511 + sodium bicarbonate solution** and water, and then dried over anhydrous magnesium sulfate. After distilling off the win, the residue was recrystallized from ethyl acetate-n-hexquinane to obtain crystals of 1.8&gt; (yield: 72 mm).

The melting point was 148-149°C. - The elemental analysis value is calculated as qN*8m to Cta 8* (
#C; 54.911. H;4.38. N;! $,!
Ill real side value @ C; 54. i13. H;4.37.
N: 5.81.

Example 3! J! Vaginal Example 4 Sodium Acid 7-A-1-A-Kyosoborate 1.30 # of salicylaldehyde was added to a pot containing 2.941 of sodium kyosoboranate dissolved in 100% of methyl alcohol, and the mixture was stirred at room temperature for 2 hours. After evaporating the solvent, the residue was dissolved in ethyl alcohol 10114 and filtered. The P solution was added dropwise to 200% of n-hexane while stirring. After 1 hour, the precipitated monochromatic crystals were taken out, washed with 30% of tohexane, and dried at 0.1 mm and ii temperature for 4 hours to obtain crystals of z, 5xy (yield: 63 bags). The melting point was 199-202°C (min.11 mol).

The element separation value is calculated as Cs v Has 0aN18Na.■ C; 51.26 H; 3.77 N;
7.04 Calculated value C @ C; 6G, 96 H; 5.8
8 N; 7.4G actual value (4) C; 6G, 90H
; S, 81 N; 7.48.

- Example 6 15801 mf of 7-(thiophene-2-acedo)cephalosporanic acid is dissolved in 10 mODMF.

Next K 404Mo) After adding ethylamine,
Misaki chloromethyl ethyl ether was added and stirred for 1 hour. After the reaction was completed, the reaction source was placed in 100i1O water. 21 with methylene chloride 080117! After extraction, the methylene chloride layer was washed with 1 liter of NaHCOs water and then with water (50 aJ). Mg804 was added to the methylene chloride layer and after drying, the solvent was distilled off under reduced pressure.

The obtained crude crystals were recrystallized from methylene chloride-n-hex/ to obtain a product of tssssy. The yield was 79. The melting point was 148-150°C.

Infrared collection spectrum 'mz(1!m-'') (Kll
y) 17B! , 174! l, 1722
Ultraviolet absorption Svetato #J, x (am) (CHC4) 61 Elemental analysis value (4): Theoretical value C; 50.21 H; 4.88 N; 6.
16 Actual column value C; 30.2 H; 4.7 N;
Get 6.3.

Example foon Example 8 7-(thiophene-2-acedoamide)cephalosporanic acid 2.0 Methyl 1,2-aminobenzoate 0.71jl
and N,N'-dicyclohexylcarbosiide 1.
05# fto5hiVay')yl 00icJIlci
The solution was stirred at room temperature for 24 hours. Generation L7
'jN, After removing N-dicyclohexyl flare, 1
゜

Claims (1)

[Claims] (1) General formula (I): (in the formula, R is 01, -Hog or -0R4 (in the formula, %R
4 represents an alkyl group or salt of H101-04) in Table 00OR. (in the formula, %R4 represents the same meaning as above). However, 1
-1] cephalosporin derivatives @(2
) General formula (I): (wherein Rs is al, -no, or -0R4 (wherein,
R4 is H, (represents a 31-C4 alkyl group or a pharmaceutically acceptable ○0OR4 or 100Hg0R4 (in the formula, R4 has the same meaning as above), but includes the following) Cephalosporin antibacterial agent whose main ingredient is a phosphorus derivative @